It has recently been discovered that certain HLA-D locus alleles have an increased frequency in patients with rheumatoid arthritis. Because it was previously known that there is no association with HLA-A or B, it appears that predisposition for development of rheumatoid arthritis is related to genes in a segment of the HLA chromosome to the left of HLA-B. This is of interest because rheumatoid arthritis is thought to have an immunologic basis and the region to the left of HLA-B probably contains the human immune response (Ir) genes. This work proposes first to establish the details of the association with HLA. Several methods will be used: typing by mixed lymphocyte culture using homozygous typing cells (HTC), typing with Primed lymphocytes (PLT) and typing by a serologic procedure for the Ia-like-antigens. Rheumatoid arthritis will be studied in three races: Caucasian, Black and Mexican-American. Other related diseases such as Sjogren's syndrome, Felty's syndrome, idiopathic pulmonary fibrosis and systemic lupus erythematosis will be investigated. The next step in this program must be investigation of the mechanism by which the genetic factors predispose for development of the disease. It is likely that the effect is through the immune response. Therefore, experiments to investigate various aspects of the immune response in vitro have been proposed. Also specific inhibition of immune fractions or products by antibodies against the Ia antigens will be studied.